chr7-55191831-T-A

Variant names:

• chr7-55191831-T-A
• rs121913444
• NM_005228.5:c.2582T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_005228.5(EGFR):​c.2582T>A​(p.Leu861Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic,drug response (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L861R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Likely pathogenic; drug response no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.98
• Publications: 2045 publications found

Genes affected

EGFR (HGNC:3236): (epidermal growth factor receptor) The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor, thus inducing receptor dimerization and tyrosine autophosphorylation leading to cell proliferation. Mutations in this gene are associated with lung cancer. EGFR is a component of the cytokine storm which contributes to a severe form of Coronavirus Disease 2019 (COVID-19) resulting from infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). [provided by RefSeq, Jul 2020]

EGFR-AS1 (HGNC:40207): (EGFR antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913
• PP5: Variant 7-55191831-T-A is Pathogenic according to our data. Variant chr7-55191831-T-A is described in ClinVar as Likely_pathogenic|drug_response. ClinVar VariationId is 163380.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGFR	NM_005228.5	c.2582T>A	p.Leu861Gln	missense_variant	Exon 21 of 28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2582T>A	p.Leu861Gln	missense_variant	Exon 21 of 28	1	NM_005228.5	ENSP00000275493.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic; drug response

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Lung adenocarcinoma Pathogenic:1

-

Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Tyrosine kinase inhibitor response Other:1

Oct 28, 2006

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: clinical testing

- Responsive

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;D;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	0.62	.;.;N
PhyloP100		8.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.3	D;.;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0090	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.48	P;.;D
Vest4		0.91
MutPred		0.60		.;.;Gain of disorder (P = 0.0189);
MVP		0.96
MPC		1.3
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.86
gMVP		0.93
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121913444; hg19: chr7-55259524; COSMIC: COSV51766344; COSMIC: COSV51766344;